The proposed research will use a novel experimental strategy to enhance our understanding of the pathophysiology of proliferative retinopathy, which is a sight-threatening complication of diabetes, retinopathy of prematurity and other important disorders. Despite the benefits of laser and anti-VEGF treatments, this complication continues to cause blindness. At present, the development of new therapeutic approaches to the problem of proliferative retinopathy is limited by gaps in knowledge about its pathophysiology. In the quest to better understand the pathophysiology of proliferative retinopathy, which is characterized by aberrant new blood vessel growth on the retinal surface, we hypothesized that pre-retinal neovessels exert a function-altering effect on the intra-retinal vasculature. By causin vascular dysfunction and thereby, compromising the effective adjustment of local perfusion to meet metabolic demand, this newly postulated pathophysiological mechanism may exacerbate retinal hypoxia, which potently stimulates neovascularization. To begin characterization of the functional interactions of pre- and intra-retinal vessels, we preformed preliminary studies utilizing a well-established mouse model of proliferative retinopathy. Building upon our extensive use of the patch-clamp technique to elucidate the functional organization of the retinal vasculature, our initial studies provided the first electrophysiological assessment of pathological neovessels in any tissue. Preliminary data support the new concept that pre-retinal neovessels exert a function-altering effect on intra- retinal vessels. To elucidate mechanisms by which pre-retinal neovessels alter the function of the intra-retinal vasculature, the specific aims of our proposed studies are to test the hypotheses that (1) in proliferative retinopathy, the membrane potential of the intra-retinal vasculature is driven to a high, function-altering level by a hyperpolarizing voltage that is transmitted from pre-retinal neovessels and (2) that proliferative retinopathy fundamentally alters how the retinal vasculature responds to the hypoxia-driven vasoactive signal adenosine. Achieving these specific aims will open up an entirely new line of scientific inquiry into the pathophysiology of proliferative retinopathy. In addition, the proposed research will create new knowledge that is likely to contribute to the development of a new therapeutic strategy for ameliorating vision loss in this disorder. In our opinion, the planned project is highly innovative because it will establish a new experimental approach for understanding proliferative retinopathy and by revealing previously unknown pathophysiological mechanisms, will significantly change current thinking about this vision-threatening disorder. In the long-term, elucidation of how proliferative retinopathy exerts function-altering effects on the intra- retinal vasculature is likely to provide new pharmacological targets for treating this dreaded complication.